Suzuki

ORGANIC LETTERS

Palladium-Catalyzed Domino C,N-Coupling/Carbonylation/Suzuki Coupling Reaction: An Efficient Synthesis of 2-Aroyl-/Heteroaroylindoles

2009 Vol. 11, No. 20 4608-4611

Martin Arthuis, Rene´e Pontikis,* and Jean-Claude Florent* Institut Curie, Centre de Recherche, 26 rue d’Ulm, Paris F-75248 cedex 05, France, and CNRS, UMR 176, 26 rue d’Ulm, Paris F-75248 cedex 05, France [email protected]; [email protected] Received August 12, 2009

ABSTRACT

A convenient one-pot synthesis of 2-aroylindoles using a domino palladium-catalyzed C,N-coupling/carbonylation/C,C-coupling sequence is described. The reaction involved easily prepared 2-gem-dibromovinylanilines and boronic acids under carbon monoxide. Optimized reaction conditions allowed the construction of a wide variety of highly functionalized 2-aroyl-/heteroaroylindoles in satisfactory yields.

The indole scaffold is prevalent in a plethora of natural and synthetic compounds characterized by a variety of biological and pharmacological activities.1 In particular, the 2-aroylindole moiety is presented in several potent tubulin polymerization inhibitors.2 In connection with our ongoing studies3 on the synthesis of new vascular disrupting agents,4 we were especially interested in the construction of polysubstituted indoles bearing a 2-aroyl or 2-heteroaroyl group. Relatively few methods for the synthesis of the 2-aroylindole skeleton have been reported. The most common (1) (a) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. ReV. 2003, 103, 893. (b) Higuchi, K.; Kawasaki, T. Nat. Prod. Rep. 2007, 24, 843. (c) Humphrey, G. R.; Kuethe, J. T. Chem. ReV 2006, 106, 2875. (2) (a) Romagnoli, R.; Baraldi, P. G.; Sarkar, T.; Carrion, M. D.; Cara, C. L.; Cruz-Lopez, O.; Preti, D.; Tabrizi, M. A.; Tolomeo, M.; Grimaudo, S.; Di Cristina, A.; Zonta, N.; Balzarini, J.; Brancale, A.; Hsieh, H.-P.; Hamel, E. J. Med. Chem. 2008, 51, 1464. (b) Mahboobi, S.; Pongratz, H.; Hufsky, H.; Hockemeyer, J.; Frieser, M.; Lyssenko, A.; Paper, D. H.; Burgermeister, J.; Bohmer, F.-D.; Fiebig, H.-H.; Burger, A. M.; Baasner, S.; Beckers, T. J. Med. Chem. 2001, 44, 4535. (3) (a) Arthuis, M.; Pontikis, R.; Florent, J. C. Tetrahedron Lett. 2007, 48, 6397. (b) Arthuis, M.; Pontikis, R.; Florent, J.-C. J. Org. Chem. 2009, 74, 2234. (c) Ty, N.; Kaffy, J.; Arrault, A.; Thoret, S.; Pontikis, R.; Dubois, J.; Morin-Allory, L.; Florent, J.-C. Bioorg. Med. Chem. Lett. 2009, 19, 1405. (4) (a) Lippert, J. W., III Bioorg. Med. Chem. 2007, 15, 605. (b) Hinnen, P.; Esken, F. Br. J. Cancer 2007, 96, 1159. 10.1021/ol901875z CCC: $40.75 Published on Web 09/18/2009

 2009 American Chemical Society

synthetic route involves regioselective addition of a variety of acyl electrophiles on an N-protected 2-lithioindole species.5 Other synthetic pathways include (a) cyclization of chalcones bearing a 2-nitrogen group,6 (b) palladiumcatalyzed coupling reactions with an acid chloride,7 and (c) palladium carbonylative cross-coupling with indoylborate.8 Moreover, these methodologies require the “de novo” construction of conveniently N-protected indoles or highly functionalized precursors. In this context, we became interested in the development of a reliable approach for the synthesis of polysubstituted 2-aroylindoles. The palladium-catalyzed domino reaction appears as an attractive synthetic route that prevents the tedious construction of elaborated precursors and enhances (5) For some examples, see: (a) Shirley, D. A.; Roussel, P. A. J. Am. Chem. Soc. 1953, 75, 375. (b) Sundberg, R. J.; Russel, H. F. J. Org. Chem. 1973, 38, 3324. (c) Saulnier, M.; Gribble, G. J. Org. Chem. 1982, 47, 757. (d) Gharpure, M.; Stoller, A.; Bellamy, F.; Firnau, G.; Snieckus, V. Synthesis 1991, 1079, and references cited therein. (6) (a) Mali, R.; Tllve, S.; Desai, V. J. Chem. Res., Miniprint 1999, 150. (b) Akazome, M.; Kondo, T.; Watanabe, Y. Chem. Lett. 1992, 21, 769. (7) (a) Labadie, S. S.; Teng, E. J. Org. Chem. 1994, 59, 4250. (b) Abbiati, G.; Casoni, A.; Canevari, V.; Nava, D.; Rossi, E. Org. Lett. 2006, 8, 4839. (8) Ishikura, M.; Terashima, M. J. Org. Chem. 1994, 59, 2634.

the efficiency of reaching the target molecules. Recently, some interesting syntheses of 2-substituted indoles via palladium-catalyzed tandem reactions, starting from 2-gemdibromovinylanilines, have emerged in the literature.9 Lautens and co-workers reported several C,N/C,C sequences providing 2-aryl,10 2-heteroaryl,11 2-alkenyl,12 or 2-alkynyl13 indoles. Interestingly, a tandem C,N/carbonylation reaction published by Alper and co-workers allowed access to various methyl-2-indolecarboxylates.14 Accordingly, we envisioned that 2-bromoindolesreported as a potential intermediate in these tandem reactionsscould generate, by the migratory insertion of carbon monoxide, an acylpalladium species which could undergo transmetalation with a boronic acid.15,16 Herein, we report an effective domino C,N-coupling/ carbonylation/C,C-coupling sequence as a new route to 2-aroyl-/heteroaroylindoles bearing a variety of functional groups. The reaction involves 2-gem-dibromovinylanilines,17 carbon monoxide, and boronic acids using palladium catalysis (Scheme 1).

Scheme 1. Strategic Approach to the Synthesis of 2-Acylindoles

The 2-gem-dibromovinylaniline 1a and phenylboronic acid 3a were chosen to investigate the feasibility of the projected reaction (Table 1). Thus, using Pd(PPh3)4, K3PO4 as a base, and toluene as the solvent under 1 atm of CO at 90 °C until consumption of the starting aniline, the desired aroylindole 2a5b could be isolated in 29% yield, but along with the 2-phenylindole18 4 (15% yield) arising from a C,N/Suzuki reaction (entry 1). Several bases were next examined, and (9) Thiegles, S.; Meddah, E.; Bisseret, P.; Eustache, J. Tetrahedron Lett. 2004, 45, 907. (10) Fang, Y.-Q.; Lautens, M. J. Org. Chem. 2008, 73, 538. (11) Fang, Y.-Q.; Karish, R.; Lautens, M. J. Org. Chem. 2007, 72, 1341. (12) Fayol, A.; Fang, Y.-Q.; Lautens, M. Org. Lett. 2006, 8, 4203. (13) Nagamochi, M.; Fang, Y.-Q.; Lautens, M. Org. Lett. 2007, 9, 2955. (14) Viera, T. O.; Meaney, L. A.; Shi, Y.-L.; Alper, H. Org. Lett. 2008, 10, 4899. (15) Carbonylative cross-coupling reactions had proved to be an efficient tool for the preparation of unsymmetrical ketones. See: (a) Brunet, J.-J.; Chauvin, R. Chem. Soc. ReV 1995, 24, 89. (b) Neigishi, E.-i. Handbook of Organopalladium Chemistry for Organic Synthesis; Ed.;Wiley-Interscience: New York, 2002; Part IV, p 2309. (c) O’Keefe, B. M.; Simmons, N.; Martin, S. F. Org. Lett. 2008, 10, 5301. (d) Brennfu¨hrer, A.; Neumann, H.; Beller, M. Angew. Chem., Int. Ed. 2009, 48, 4114. (16) For recent examples of carbonylation used in combination with alternative palladium-catalyzed reactions, see: (a) Awuah, E.; Capretta, A. Org. Lett. 2009, 11, 3210. (b) Tadd, A. C.; Matsuno, A.; Fielding, M. R.; Willis, M. C. Org. Lett. 2009, 11, 583. (c) Chouhan, G.; Alper, H. Org. Lett. 2008, 10, 4987. (d) Martinelli, J. R.; Watson, D. A.; Freckmann, D. M. M.; Barder, T. E.; Buchwald, S. L. J. Org. Chem. 2008, 73, 7102, and references cited therein. (e) Worlikar, S. A.; Larock, R. C. J. Org. Chem. 2008, 73, 7175. (f) Grigg, R.; Sridharan, V.; Saha, M.; Mutton, S.; Kilner, C.; Macpherson, D.; Milner, P. J. Org. Chem. 2008, 73, 8352. (17) For a recent review on the site-selective cross-coupling of dihalogenated compounds, see: Wang, J. R.; Manabe, K. Synthesis 2009, 1405. (18) Augustine, R. L.; Gustavsen, A. J.; Wanat, S. F.; Pattison, I. C.; Houghton, K. S.; Koletar, G. J. Org. Chem. 1973, 38, 3004. Org. Lett., Vol. 11, No. 20, 2009

Table 1. Optimization of the Reaction Conditionsa

entry solvent basea

CO

catalyst Pd(PPh3)4 Pd(PPh3)4 Pd(PPh3)4 Pd(PPh3)4 Pd(PPh3)4c PdCl2dppfc Pd2dba3/ Xantphosc Pd(PPh3)4 Pd(PPh3)4 Pd(PPh3)4 Pd(PPh3)4 Pd(PPh3)4

1 2 3 4 5 6 7

toluene toluene toluene toluene toluene toluene toluene

K3PO4 K2CO3 Cs2CO3 CsF K2CO3 K2CO3 K2CO3

balloon balloon balloon balloon balloon balloon balloon

8 9 10 11 12

toluene dioxane dioxane dioxane dioxane

K2CO3 K2CO3 K2CO3 K2CO3 K2CO3

12 12 12 12 12

bar bar bar bar bar

temp yield (°C)/time (h) 2a/4 (%)b 90/6 90/24 90/24 90/48 90/2 90/18 90/18

29/15 45/7 25/2 trace 45/25 28/8 12/6

110/16 100/16 85/24 85/48 85/60

44/0 61/0 54/0 62/0 70/0

a All reactions were performed on a 1 mmol scale using 5 mol % of catalyst, 5 equiv of base, and 1.1 equiv of phenylboronic acid. b Isolated yield after column chromatography. c 3 equiv of KI was added.

K2CO3 proved to be the most efficient (entries 2s45% yieldsvs 1, 3, and 4). Other catalyst systems did not favor the expected threestep tandem process (entries 5-7).19 To promote the carbonylation step, the domino reaction was performed under 12 bar of CO (entries 8-12). Using this relatively low pressure, the sequence provided exclusively 2-benzoylindole 2a (entry 8, 44% yield). Exchanging toluene to dioxane at 100 °C resulted in a higher yield of 2a (entry 9, 61%), but a longer heating time did not improve the coupling efficiency (data not shown). Reducing the temperature to 85 °C resulted in a slight diminution of the yield (entry 10, 54%), while heating for a longer time (48 or 60 h) allowed recovery of up to 70% yield for product 2a (entries 11 and 12). Modification of the catalytic system also failed to improve the yield (data not shown). To examine the scope of this one-pot protocol, we selected the optimized reaction conditions (K2CO3, Pd(PPh3)4, CO 12 bar, dioxane) and chose the temperature/time parameters with respect to the nature of the engaged substrates. For substituted anilines 1b-1g,20 which are prone to degradation, domino reactions were conducted at 85 °C for 24 h. As highlighted in Table 2, several functional groups are tolerated including chlorine (entry 1, 68%), the electron-withdrawing methoxycarbonyl group (entry 2, 50%), or electron-releasing groups (entries 4-6) to produce benzoylindoles 2b-2f2b,6a in good yields. The reaction can also be conducted with the polysubstituted aniline 1g to provide 2-benzoyl-4,5,6-trimethoxindole 2g in (19) KI and dppf complex were reported to enhance the carbon monoxide insertion vs the transmetalation of boronic acids, see: Ishiyama, T.; Kizaki, H.; Hayashi, T.; Suzuki, A.; Miyaura, N. J. Org. Chem. 1998, 63, 4726. (20) gem-Dibromovinylanilines 1b-1g were prepared in a two-step sequence (Ramirez olefination, reduction using SnCl2·2H2O) from onitrobenzaldehyde derivatives according to Fang and Lautens (see ref 10). 4609

Table 2. Variation of the 2-gem-Dibromovinylanilinesa

Table 3. Scope of Aryl Boronic Acidsa

a All reactions were performed on a 1 mmol scale using 5 mol % of Pd(PPh3)4, 5 equiv of K2CO3, and 1.1 equiv of phenyl boronic acid under an atmosphere of CO (12 bar). b Isolated yield after column chromatography. c Reaction run at 100 °C for 16 h.

good yield (entry 6, 65%). It is noteworthy that yields could be further enhanced by increasing the reaction time. We then turned our attention to the scope of aryl boronic acids. Since the starting aniline 1a was robust enough, these reactions were conducted at higher temperature (100 °C) for 16 h using several commercially available boronic acids 3h-3o (Table 3). Electron-rich partners, such as 4-methoxyphenyl or 3,4,5-trimethoxyphenyl boronic acids, performed well under the optimized conditions (entries 1 and 2).2b,21 The reaction seems to be sensitive to steric hindrance imposed by the o-substitution of the boronic acid. For example, 2-methoxyphenylboronic acid 3j furnished the aroylindole 2j21 in modest yield (entry 3, 40%), whereas with the 2,6dimethylphenylboronic acid, an attempt to isolated indole 2k was unsuccessful despite complete consumption of aniline 1a (entry 4). Electron-deficient substrates, such as 4-trifluoromethyl or 4-chlorophenylboronic acids, react smoothly (entries 5-6, 73 and 70%, respectively).22 Boronic acid 3n, bearing an amido group, participates in the reaction albeit (21) Katritzky, A. R.; Akutagawa, K. Tetrahedron Lett. 1985, 26, 5935. 4610

a All reactions were performed on a 1 mmol scale using 5 mol % of Pd(PPh3)4, 5 equiv of K2CO3, and 1.1 equiv of boronic acid under an atmosphere of CO (12 bar). b Isolated yield after column chromatography.

in a lower yield (entry 7, 29%). Phenylvinylboronic acid also proved to be an efficient partner of the domino reaction providing indol-2-ylchalcone 2o in good yield (entry 8, 67%). Finally, we explored the application of the domino reaction to heteroarylboronic acids (Table 4). The reaction proved to be compatible with various substrates such as thiophen-3-, benzofuran-2-, or dibenzofuran-4-boronic acids providing 2-heteroaroylindoles 2p-2s2b,23 in fair to good yields (entries 1-3, 58-71%). Reaction with isoquinolin-3-boronic acid was less efficient providing indole 2s in low yield, probably due to the nitrogen of the boronic acid (entry 4, 21%). (22) Takeda, Y.; Kikuchi, A.; Terashima, M. Heterocycles 1993, 35, 573. Org. Lett., Vol. 11, No. 20, 2009

Table 4. Scope of Heteroaryl Boronic Acidsa

2-Naphthylboronic acid also participated in the domino process leading to polycyclic compound 2t24 in good yield (entry 5, 70%). In summary, we have established a novel and efficient protocol for the preparation of 2-aroylindoles in moderate to good yields, through a one-pot palladium-catalyzed C,N-coupling/carbonylation/Suzuki coupling sequence. The reaction tolerates various functional groups, thus providing a practical access to a wide range of 2-aroylor 2-heteroaroylindoles from readily accessible starting materials. The application of this methodology to the synthesis of bioactive compounds is underway in our laboratory. Acknowledgment. This work was financially supported by the Centre National de la Recherche Scientifique, the Institut Curie, and INCa. M.A. thanks the Ministe`re de l’Enseignement Supe´rieur et de la Recherche for a Ph.D. Fellowship Grant. Supporting Information Available: Synthetic procedures, characterization data, and copies of the 1H NMR and 13C NMR experiments. This material is available free of charge via the Internet at http://pubs.acs.org. OL901875Z

a All reactions were performed on a 1 mmol scale using 5 mol % of Pd(PPh3)4, 5 equiv of K2CO3, and 1.1 equiv of boronic acid under an atmosphere of CO (12 bar). b Isolated yield after column chromatography.

Org. Lett., Vol. 11, No. 20, 2009

(23) Mahboobi, S.; Uecker, A.; Cenac, C.; Sellmer, A.; Eichhorn, E.; Elz, S.; Bo¨hmer, F.-D.; Dove, S. Bioorg. Med. Chem. 2007, 15, 2187. (24) Kar, S.; Lahiri, S. J. Indian. Chem. Soc. 1999, 76, 607.

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